WO1995018805A1 - Compose d'acide 1,4-benzoxazine-2-acetic, son procede de production et son utilisation - Google Patents

Compose d'acide 1,4-benzoxazine-2-acetic, son procede de production et son utilisation Download PDF

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Publication number
WO1995018805A1
WO1995018805A1 PCT/JP1994/000005 JP9400005W WO9518805A1 WO 1995018805 A1 WO1995018805 A1 WO 1995018805A1 JP 9400005 W JP9400005 W JP 9400005W WO 9518805 A1 WO9518805 A1 WO 9518805A1
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WO
WIPO (PCT)
Prior art keywords
methyl
dihydro
oxo
acetic acid
benzoxazine
Prior art date
Application number
PCT/JP1994/000005
Other languages
English (en)
Japanese (ja)
Inventor
Takahiro Kumonaka
Takema Hase
Tomoji Aotsuka
Toshio Kurihara
Yoshiyuki Nakamura
Tetsuo Matsui
Hiromichi Ishikawa
Fujio Kobayashi
Original Assignee
Senju Pharmaceutical Co., Ltd.
The Green Cross Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to CA000345502A priority Critical patent/CA1143367A/fr
Priority claimed from JP4274827A external-priority patent/JPH06172353A/ja
Priority to JP4274827A priority patent/JPH06172353A/ja
Priority to DE69428457T priority patent/DE69428457D1/de
Priority to KR1019960703599A priority patent/KR100298003B1/ko
Priority to AT94903999T priority patent/ATE206121T1/de
Application filed by Senju Pharmaceutical Co., Ltd., The Green Cross Corporation filed Critical Senju Pharmaceutical Co., Ltd.
Priority to AU58232/94A priority patent/AU684260B2/en
Priority to US08/666,326 priority patent/US5635505A/en
Priority to PCT/JP1994/000005 priority patent/WO1995018805A1/fr
Priority to EP94903999A priority patent/EP0738727B1/fr
Priority to CA002180340A priority patent/CA2180340A1/fr
Priority to TW083100330A priority patent/TW309519B/zh
Publication of WO1995018805A1 publication Critical patent/WO1995018805A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a novel 1,4-benzoxazine-12-acetic acid compound having excellent aldose reductase inhibitory activity, a pharmaceutically acceptable salt thereof, a method for producing the same, and a pharmaceutical use thereof. Further, the compound of the present invention and a pharmaceutically acceptable salt thereof are useful as preventive and therapeutic agents for diabetic complications such as diabetic cataract, retinopathy, nephropathy, and neuropathy.
  • blood glucose regulators such as insulin and synthetic hypoglycemic agents have been widely used as therapeutic drugs for diabetes.
  • Diabetes is a disease accompanied by various complications. It is difficult to prevent, and new drugs for diabetes complications are needed.
  • compounds that inhibit the activity of aldose reductase an enzyme that reduces aldoses such as glucose and galactose to sorbitol and galactitol, may be used for diabetes such as cataract, neurosis, retinopathy, etc. It has been suggested in the literature to be useful in the treatment of complications [JH Kinoshita et al., Biochem.
  • Japanese Patent Application Laid-Open No. 61-204264 and And Japanese Patent Application Laid-Open No. 63-179790 describe that various 1,4-benzothionidine-4-monoacetic acid compounds have an aldose reductase inhibitory action.
  • development of a preventive / therapeutic agent for diabetic complications having even better aldose reductase inhibitory activity is desired.
  • the present inventors have conducted intensive studies to develop a preventive / therapeutic agent for glycemic complications having an aldose reductase inhibitory effect, and a certain benzoxazine compound achieves the object. With this finding, the present invention has been completed. That is, the present invention provides a compound represented by the general formula (I):
  • R 1 , R 2 and R 3 may be the same or different and each represents a hydrogen atom, a lower alkyl group, an alkoxy group, a halogen atom or a hydroxyl group, and R 4 represents a hydrogen atom, a halogen atom, It represents an alkyl group or an alkoxy group, and R 5 represents a carboxyl group which may be esterified.
  • the present invention provides the following:
  • R 1 , R 2 and R 3 have the same meanings as described above, and Y is a halogen atom or 100 S 0 2 Rs (where R s is a lower alkyl group, a trifluoromethyl group or A phenyl group which may be substituted). Or a compound represented by the formula
  • R 1 , R 2 and R 3 are each as defined above.
  • the compound represented by the above general formula (B) is characterized by reacting the compound obtained in the above (a) or (b) with a hydrolysis reaction if necessary.
  • the present invention relates to a method for producing a 1,4-benzoxazine-12-acetic acid compound represented by I) or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the above 4-benzoxazine-12-acetic acid compound or a pharmaceutically acceptable salt thereof, and more particularly to an aldose reductase P and a diabetic complication preventive agent. ⁇ Regarding therapeutic agents.
  • the compound of the present invention represented by the above general formula (I) (hereinafter referred to as the compound of the present invention (I) Is a compound having a novel structure that requires a 1,4-benzoxazine-12-acetic acid moiety as a basic structure.
  • Examples of the halogen atom in R 1 to R 4 and Y include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the lower alkyl group for R 1 ⁇ R 4, R 6, preferably a linear Oh Rui branched alkyl group having 1 to 6 carbon atoms, such as methyl, Echiru, propyl, I an isopropyl, butyl, isobutyl, Examples include sec-butyl, tert-butyl, ventil, isopentyl, sec-pentyl, tert-pentyl, hexyl, isohexyl, sec-hexyl and tert-hexyl. Further, these lower alkyl groups may be substituted with an aryl group, an amino group, a halogen atom (the same as described above), and the like.
  • alkoxy group for R 1 to R 4 a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms is preferable.
  • these alkoxy groups may be substituted with an aryl group, an amino group, a halogen atom (the same as described above), and the like.
  • esterified carboxyl group in R 5 examples include lower alkoxycarbonyl such as methoxycarbonyl, ethoxyquincarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, and benzene.
  • Examples include aryloxycarbonyl or benzyloxycarbonyl which may have a substituent on the ring.
  • substituent in aryloxycarbonyl which may have a substituent on the benzene ring include a halogen atom (the same as described above), an alkyl group, an alkoxyl group, and a nitro group.
  • substituent for the optionally substituted phenyl group in R 6 examples include an alkyl group (same as above), a halogen atom (same as above), and a nitro group.
  • R 1 , R 2 and R 3 in the general formula (I) can take any position of the benzothiazolyl group at the 4th to 7th positions, preferably at the 4th, 5th and 7th positions. Further, it is preferable that at least one of R 1 , R 2 and R 3 is a halogen atom, and it is particularly preferable that the halogen atom is a fluorine atom.
  • R 4 in the general formula (I) can take any position at the 5 to 8 position of the benzoxazine ring, preferably at the 6 or 7 position.
  • R ⁇ is preferably a hydrogen atom, a lower alkyl group or a halogen atom, and most preferably a hydrogen atom, a methyl group, a chlorine atom or a fluorine atom.
  • - 5 in general formula (I) is preferably a carboxyl group.
  • the compound (I) of the present invention has an asymmetric carbon atom, and therefore can exist as a stereoisomer, and these are also included in the present invention. These can be separated into pure isomers by a conventional method, if necessary.
  • Pharmaceutically acceptable salts of the compound (I) of the present invention include, for example, inorganic bases (eg, alkali metals such as lithium, sodium and potassium, alkaline earth metals such as calcium, magnesium and beryllium, and aluminum). Or salts with organic bases (eg, triethylamine, pyridine, etc.).
  • inorganic bases eg, alkali metals such as lithium, sodium and potassium, alkaline earth metals such as calcium, magnesium and beryllium, and aluminum.
  • organic bases eg, triethylamine, pyridine, etc.
  • Typical examples of the compound (I) of the present invention include the following compounds.
  • R 1 i R 2 and R 3 are each as defined above, and Y is a halogen atom (Wherein, R e is a lower alkyl group, a triflate Ruo b methyl group or an optionally substituted Fuyuniru group) child or single OS_ ⁇ 2 R e indicates a.
  • the compound of the present invention (I) is produced by reacting the compound represented by the formula (1) with a basic condition and / or under an inert gas atmosphere, if necessary, and further subjecting it to a hydrolysis reaction, if necessary. be able to.
  • Suitable examples of the salt of the compound represented by the general formula (IT) include the above-mentioned pharmaceutically acceptable salts.
  • the base under the above basic conditions is an inorganic base (eg, an alkali metal such as lithium, sodium, potassium, an alkaline earth metal such as beryllium, magnesium, calcium, etc., an alkali metal hydride such as sodium hydride, hydride Alkaline earth metal hydrides such as calcium, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, sodium bicarbonate and sodium bicarbonate Metal bicarbonate, alkali metal alkoxide such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, alkali metal alkanoate such as sodium acetate, etc., organic base (eg, triethylamine, etc.) Trialkylamine, pyridine, lutidine, picoline .
  • an inorganic base eg, an alkali metal such as lithium, sodium, potassium, an alkaline earth metal such as beryllium, magnesium, calcium
  • Pyridine compounds such as 4-dimethylaminopyridine, quinoline and the like).
  • the inert gas refers to nitrogen, argon, and the like.
  • the above reactions are usually carried out in a variety of solvents such as dichloromethane, methanol, ethanol, propanol, pyridine, N, N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and other conventional solvents which do not adversely affect the reaction. It is performed in a solvent or a mixture thereof. Preferred solvents include N, N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide.
  • the reaction temperature is not particularly limited, but the reaction is usually performed in a range from under cooling to heating. For example, when potassium carbonate is used as the base, the reaction temperature is preferably 0'C to room temperature.
  • the hydrolysis reaction is carried out by a usual process in the presence of a base or an acid, if necessary.
  • Suitable bases include, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and alkali metal carbonates such as sodium carbonate and potassium carbonate.
  • Suitable acids include organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, benzenesulfonic acid and p-toluenesulfonic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid.
  • the base or acid used in a liquid state, it is also used as a solvent, and furthermore, water, acetone.
  • Dioxane, dichloromethane, methanol, ethanol, propanol, pyridine, N , N-dimethylformamide and the like can be carried out in a conventional solvent which does not adversely affect the reaction, or a mixture thereof.
  • the reaction temperature is not particularly limited, and the reaction is performed in a range from under cooling to under heating.
  • the starting compound represented by the general formula (I) is a known substance or a known method [Chemical & Pharmaceutical Bulletin, 34 (1), 130- 139. 1986].
  • the starting compound represented by the general formula ( ⁇ ) is a known compound or a known method (refer to Journal of Medicinal Chemistry, 34. 108-122. 1991). Can be manufactured more easily.
  • the compound (I) of the present invention can be produced by reacting the compound represented by the formula (I) or an acid addition salt thereof in the presence of an acid, if necessary, and further subjecting it to a hydrolysis reaction, if necessary. it can.
  • the salt of the compound represented by the general formula (IV) preferably includes the above-mentioned pharmaceutically acceptable salts.
  • Preferred solvents in the above reaction include methanol, ethanol, propanol and the like.
  • the acid examples include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and nitric acid, and organic acids such as formic acid, acetic acid, and poronic acid. Among them, strong acids such as sulfuric acid and hydrochloric acid are preferred.
  • the reaction temperature is not particularly limited, but is preferably from 6 O'C to reflux temperature.
  • the compound of the general formula (W) can be combined with a compound of the general formula (V), preferably an acid addition salt thereof (hydrochloride or the like), and a compound of 130 to 18 O'C
  • the reaction may be performed by eutectic at a temperature.
  • the hydrolysis reaction is carried out under the same reaction conditions as in the above-mentioned production method (a).
  • the starting compound represented by the general formula (IV) is a compound of the formula (H)
  • Z represents a halogen atom (the same as described above).
  • the base under the above basic conditions includes, for example, alkali metal hydrides such as sodium hydride, alkaline earth metal hydrides such as calcium hydride, sodium hydroxide, Alkali metal hydroxides such as hydroxylated lime, alkali metal carbonates such as sodium carbonate and carbonated lime, alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate, sodium methoxide, sodium ethkind Metal alkoxides such as potassium tertiary butoxide and the like; metal salts of alkali metal salts such as sodium acetate and the like.
  • alkali metal hydrides such as sodium hydride
  • alkaline earth metal hydrides such as calcium hydride, sodium hydroxide
  • Alkali metal hydroxides such as hydroxylated lime
  • alkali metal carbonates such as sodium carbonate and carbonated lime
  • alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate
  • sodium methoxide sodium ethkind Metal alkoxide
  • the inert gas refers to nitrogen and argon.
  • the above reaction usually does not adversely affect the reaction of various solvents such as dichloromethane, methanol, ethanol, bronbanol, pyridine, N, N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, etc. It is carried out in customary solvents or mixtures thereof. Preferred solvents include N, N-dimethylformamide, tetrahydrofuran, and dimethylsulfoxide.
  • the reaction temperature is not particularly limited, but is preferably room temperature to 100.
  • the raw material compound represented by the general formula (V) is a known substance or a known method [refer to Journal of Medicinal Chemistry. 34. 108-122, 1991]. Can be manufactured more easily.
  • the compound (I) of the present invention obtained by the above production method can be isolated and purified by a conventional method such as extraction, precipitation, fractional chromatography, fractionation, crystallization, and recrystallization.
  • the compound (I) of the present invention thus produced can be converted into a pharmaceutically acceptable salt by a conventional method, if desired.
  • Aldose reductase enzyme preparations were prepared from Hyman (S.
  • Test compound Compound of the present invention and compound A (3,4-dihydro-2,8-diisopropyl-13-thioxo 2H-1,4-benzoxazine described in JP-A-63-179790) 4 monoacetic acid)
  • Aldo-slidacose was measured by the method of Hyman et al. Described above. That is, a final concentration of 0.4 M lithium sulfate, 0.1 lmM NADPH (reduced
  • nicotinamide adenine dinucleotide phosphate ⁇ and 4 OmM phosphate buffer ( ⁇ 6.2) prepared to contain 3 mM til-glyceraldehyde as a substrate.
  • Various concentrations of drug solutions 25 dissolved in ⁇ (dimethyl sulfoxide) were added, respectively. Thereafter, the mixture was reacted at 25'C for 2 minutes, and the change in absorbance at 340 nm was measured using COBAS FARAI [manufactured by Kuchishash Corporation].
  • the change in absorbance when l% DMSO was added instead of the drug solution was set to 100%, and the results are shown in Table 1 as 50% inhibitory concentrations (ICso) of the drug.
  • the test drug number indicates the example number described later.
  • the IC 50 value (M) represents the concentration of a drug that inhibits aldose reductase activity by 50 %.
  • Test drug Compound of the present invention and compound A (3,4-dihydro-2,8-diisopropyl-13-thioxo-1 2H-1,4-benzobenzoxine-monoacetic acid described in JP-A-63-107970)
  • Sprague-Dawley rats male, 6 weeks old, 5-6 rats / group were fasted for 18 hours, and injected with streptobutcin (SI GMA) 6 OmgZkg into the tail vein under ether anesthesia. Diabetic rats were produced.
  • the various test drugs were orally administered with 10 or 3 OmgZkg as a 0.5% carboxymethylcellulose suspension, respectively, at 4, 8 and 24 hours after the injection of streptobutcin.
  • the rats were maintained on food and water ad libitum and 3 hours after the final administration, the sorbitol content in the tissues (erythrocytes, sciatic nerve, lens) was determined by the method of HY Bergmeyer et al. Enzymatic analysis (Methods of Enzymatic Analysis). See 3. 1323-1330, 1974] and SDH (sorbitol dehydrogenase) and NAD (9-nicotinamide adenine). dinucleotide).
  • the measurement result (sorbitol accumulation rate) was expressed as a percentage (1 ⁇ 2) when the value of the control group to which a 0.5% carboxymethylcellulose solution as a solvent was administered instead of the drug was taken as 100%. Table 2 shows the results.
  • mice Male, 7 weeks old, 5 mice per group were fasted for 18 hours and then orally administered with 30 OmgZkg of the compound of Example 33 as a 0.5% carboxymethylcellulose suspension.
  • the control group received only 0.5% carboxymethylcellulose solution. Mouth administration was followed by observation for 14 days. During this time, mice were fed with food and water ad libitum.
  • the compound of the present invention and a pharmaceutically acceptable salt thereof have an excellent inhibitory activity on aldose reductase and are also excellent in safety. It is useful for mammals such as mice and rats as a preventive and therapeutic agent for diabetic complications such as corneal damage fusion defect, cataract, neuropathy, retinopathy, and renal disorder. It is useful as a preventive and therapeutic agent.
  • the compound of the present invention and a pharmaceutically acceptable salt thereof are administered for the purpose of preventing or treating the above-mentioned diseases, they can be administered orally or parenterally.
  • the compound of the present invention and a pharmaceutically acceptable salt thereof may be used in the form of solid, semi-solid and liquid preparations containing an organic or inorganic carrier suitable for external use, oral administration or topical administration and a Z or II drug.
  • the compounds of the present invention and their salts provide, together with non-toxic and pharmaceutically acceptable auxiliary ingredients, appropriate dosage forms such as tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions and the like.
  • auxiliary ingredients include solids, such as, for example, water, glucose, lactose, gelatin, mannitol, starch paste, magnesium trigeate, corn starch, keratin, colloidal silica, potato starch, urea, and the like.
  • auxiliary substances such as stabilizers, extenders, colorants and fragrances can be included.
  • the above-mentioned preparations can also contain a preservative in order to maintain the activity of the compound of the present invention and salts thereof, so as to produce a desired prophylactic / therapeutic effect on the progress or disease state of a related disease. It should contain a sufficient amount of the compound of the present invention and salts thereof.
  • an amount effective to inhibit aldose reductase or an amount effective to prevent or treat diabetic complications is desirable.
  • it is administered by injection, eye drop or orally.
  • the dosage of the compound of the present invention and salts thereof varies depending on age, body weight, symptoms, preventive and therapeutic effects, administration method, administration period, and the like. However, in the case of oral administration, it is usually 1 to 2000 mgZ days, preferably. Is preferably administered in a dose range of 10 to 60 OmgZ days, 1 to 3 times a day.
  • the above components were uniformly mixed, 200 ml of a 7.5% aqueous solution of hydroxypropyl cellulose was added, granulated using a screen with a diameter of 0.5 mm by an extrusion granulator, immediately rounded with a mamizer, and dried.
  • the dried granules were coated with 1.9 kg of a film coating solution having the following composition using a fluidized granulator to obtain enteric granules.
  • the above-mentioned components were uniformly mixed and made into tablets of 20 Omg per tablet with a single punch using a punch having a diameter of 7.5 mm.
  • the tablets were spray-coated with a coating solution having the following composition, and coated at 1 Omg per square meter to give enteric film-coated tablets.
  • Coating liquid composition Hydroxybutyl pill methyl cellulose phthalate 8.0 (W / W)% Mino, 'Set 0.4 (WZW)% Methylene chloride 50.0 (W / W)% Salami beeswax 0.1 (W / W)% Isopropanol 41.5 (W / W)% Formulation Example 3
  • 1 capsule was prepared by a rotary method using a coating solution for soft capsules consisting of 100 parts of gelatin, 30 parts of concentrated glycerin, 0.4 parts of ethylparaben and 0.2 parts of propylparaben. A soft capsule containing 0 Omg of the drug solution was used.
  • the total amount was 100 ml.
  • An ophthalmic solution was prepared according to the above formulation in a conventional manner.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composé d'acide 1,4-benzoxazine-2-acétique représenté par la formule générale (I) ou un sel médicinalement acceptable de celui-ci, son procédé de production et composition médicinale le contenant, comprenant un inhibiteur d'aldose réductase ainsi qu'un médicament de prévention ou de traitement de complications du diabète. La définition de chaque symbole figure dans la description. Le composé (I) ainsi que le sel présentent une activité d'inhibiteur d'aldose réductase ainsi qu'une excellente sécurité, par conséquent ils sont utiles en tant que médicament de prévention ou de traitement de complications du diabète, telles que la mauvaise conjonction de lésions de la cornée, de la cataracte, de la névrose, la rétinopathie et de la néphropathie, et en particulier de la cataracte et de la névrose.
PCT/JP1994/000005 1980-02-12 1994-01-06 Compose d'acide 1,4-benzoxazine-2-acetic, son procede de production et son utilisation WO1995018805A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
CA000345502A CA1143367A (fr) 1980-02-12 1980-02-12 Element diffuseur
JP4274827A JPH06172353A (ja) 1992-09-21 1992-09-21 １，４−ベンゾオキサジン−２−酢酸誘導体及びそれを含有する糖尿病合併症治療剤
CA002180340A CA2180340A1 (fr) 1992-09-21 1994-01-06 Compose d'acide 1,4-benzoxazine-2-acetic, son procede de production et son utilisation
KR1019960703599A KR100298003B1 (ko) 1994-01-06 1994-01-06 1,4-벤즈옥사진-2-아세트산화합물,그의제조방법및용도
AT94903999T ATE206121T1 (de) 1980-02-12 1994-01-06 1,4-benzoxazin-2-essigsäureverbindung, verfahren zu ihrer herstellung und ihre verwendung
DE69428457T DE69428457D1 (de) 1980-02-12 1994-01-06 1,4-benzoxazin-2-essigsäureverbindung, verfahren zu ihrer herstellung und ihre verwendung
AU58232/94A AU684260B2 (en) 1992-09-21 1994-01-06 1,4-benzoxazine-2-acetic acid compound, process for producing the same, and use thereof
US08/666,326 US5635505A (en) 1994-01-06 1994-01-06 1,4-benzoxazine-2-acetic acid compound, method for production thereof and use thereof
PCT/JP1994/000005 WO1995018805A1 (fr) 1992-09-21 1994-01-06 Compose d'acide 1,4-benzoxazine-2-acetic, son procede de production et son utilisation
EP94903999A EP0738727B1 (fr) 1992-09-21 1994-01-06 Compose d'acide 1,4-benzoxazine-2-acetic, son procede de production et son utilisation
TW083100330A TW309519B (fr) 1992-09-21 1994-01-17

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP4274827A JPH06172353A (ja) 1992-09-21 1992-09-21 １，４−ベンゾオキサジン−２−酢酸誘導体及びそれを含有する糖尿病合併症治療剤
CA002180340A CA2180340A1 (fr) 1992-09-21 1994-01-06 Compose d'acide 1,4-benzoxazine-2-acetic, son procede de production et son utilisation
PCT/JP1994/000005 WO1995018805A1 (fr) 1992-09-21 1994-01-06 Compose d'acide 1,4-benzoxazine-2-acetic, son procede de production et son utilisation

Publications (1)

Publication Number Publication Date
WO1995018805A1 true WO1995018805A1 (fr) 1995-07-13

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PCT/JP1994/000005 WO1995018805A1 (fr) 1980-02-12 1994-01-06 Compose d'acide 1,4-benzoxazine-2-acetic, son procede de production et son utilisation

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63230689A (ja) * 1987-03-18 1988-09-27 Tanabe Seiyaku Co Ltd ベンゾオキサジン誘導体
JPS63270678A (ja) * 1987-04-30 1988-11-08 Mitsui Petrochem Ind Ltd 新規含窒素化合物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63230689A (ja) * 1987-03-18 1988-09-27 Tanabe Seiyaku Co Ltd ベンゾオキサジン誘導体
JPS63270678A (ja) * 1987-04-30 1988-11-08 Mitsui Petrochem Ind Ltd 新規含窒素化合物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0738727A4 *

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